The substance was first described in the document WO 9837075. Its preparation procedure in accordance with the above mentioned document is shown in Scheme 1.
In the first production stage the chloride of compound I reacts with compound II in tetrahydrofuran using triethylamine as a base. Substance III is the product of the reaction. During a reproduction of the above mentioned procedure substance III was obtained in the base form. However, in our experience and in accordance with WO 9837075 this substance requires complex purifying operations, e.g. chromatography, in order to be used for the production of high-quality API.
The next production stage is reduction of the nitro group to the amino group. In the document WO 9837075 this reaction is performed by means of catalytic hydrogenation with the use of palladium on active carbon under high pressure. However, this process has very high technological demands and manifests safety and environmental risks. It requires the use of high pressure and therefore special equipment is necessary. The catalysts used are toxic and their price together with the price of the equipment is very negatively reflected in the economy of the whole process. Another disadvantage of this process is a very low quality of the product of formula IV obtained this way. This way the product is obtained in an oily form with the content of impurities of 20-40%. Product IV, at least according to the known process, must enter the next stage in a contaminated form. Finding an alternative method of performing this reaction would certainly represent a great contribution to making the production of dabigatran more efficient.
In the third stage substance IV reacts with substance V, producing substance VI. According to WO 9837075 compound V is prepared by a reaction of 4-cyanophenyl aniline with chloroacetic acid in the presence of a base. During a reproduction of the procedure of WO 9837075 we found out that the reaction provides a low yield (about 50%). The product of the procedure in accordance with WO 9837075 is compound VI in the base or acetate form. Both these products require chromatographic purification, which is very difficult to implement in the industrial scale.
In the next stage acidic hydrolysis of the nitrile function of compound VI and reaction with ammonium carbonate producing compound VII is carried out. The last stage is a reaction of intermediate VII with hexyl chloroformate producing dabigatran.
